Heteroaryl carboxamides

ABSTRACT

The invention relates to novel heteroaryl carboxamides, a process for their preparation, and pharmaceutical compositions containing them. These materials are useful for the treatment and/or prophylaxis of diseases and for improving perception, concentration, learning and/or memory.

This application is a Continuation application of U.S. application Ser.No. 10/496,404 filed on May 13, 2004, which is a 371 of PCT/EP02/12375filed Nov. 6, 2002, which claims priority to German Patent ApplicationNo. 101 56 719.7 filed Nov. 19, 2001, the contents of each of which areincorporated herein by reference.

The invention relates to novel heteroaryl carboxamides, processes fortheir preparation, and their use for producing medicaments for thetreatment and/or prophylaxis of diseases and for improving perception,concentration, learning and/or memory.

Nicotinic acetylcholine receptors (nAChR) form a large family of ionchannels which are activated by the messenger acetylcholine which isproduced in the body (Galzi and Changeux, Neuropharmacol. 1995, 34,563-582). A functional nAChR consists of five subunits which may bedifferent (certain combinations of α1-9 and β1-4,γ,δ,ε subunits) oridentical (α7-9). This leads to the formation of a diversity of subtypeswhich differ in the distribution in the muscles, the nervous system andother organs (McGehee and Role, Annu. Rev. Physiol. 1995, 57, 521-546).Activation of nAChR leads to influx of cations into the cell and tostimulation of nerve cells or muscle cells. Selective activation ofindividual nAChR subtypes restricts this stimulation to the cell typeswhich have the corresponding subtype and is thus able to avoid unwantedside effects such as, for example, stimulation of nAChR in the muscles.Clinical experiments with nicotine and experiments in various animalmodels indicate that central nicotinic acetylcholine receptors areinvolved in learning and memory processes (e.g. Rezvani and Levin, Biol.Psychiatry 2001, 49, 258-267). Nicotinic acetylcholine receptors of thealpha7 subtype (α7 nAChR) have a particularly high concentration inregions of the brain which are important for learning and memory, suchas the hippocampus and the cerebral cortex (Séguéla et al., J. Neurosci.1993, 13, 596-604). The α7 nAChR has a particularly high permeabilityfor calcium ions, increases glutamatergic neurotransmission, influencesthe growth of axons and, in this way, modulates neuronal plasticity(Broide and Leslie, Mol. Neurobiol. 1999, 20, 1-16).

WO 85/01048 and DE-A-3724059 describe certain heteroaryl carboxamides asserotonin M or 5HT₃ antagonists for the treatment of arrhythmias andpain, and psychoses and disorders of consciousness.

EP-A-0 327 335 discloses certain heteroaryl carboxamides with amemory-improving effect.

Isoquinolinecarboxamides with an 5HT₃-antagonistic effect are disclosedin WO 91/17161 for the treatment of CNS disorders.

WO 01/60821 discloses biaryl carboxamides with affinity for the α7 nAChRfor the treatment of disorders of learning and perception.

Certain 2- and 3-quinolinecarboxamides are described in Orjales et al.Drug Des. Discovery 2000, 16, 271-279 as ligands on the 5HT₃ receptor.

The present invention relates to compounds of the general formula (I)

in which

-   R¹ is an azabicyclo[m.n.o]alkyl radical having 7 to 11 ring atoms,    in which m, n and o are identical or different and are 0, 1, 2 or 3,    and where the radical is optionally substituted by (C₁-C₆)-alkyl,-   the ring A is pyrimido, or    -   is optionally benzo-fused pyrido, pyridazo or pyridazino, and-   R² and R³ are identical or different and are radicals selected from    the group of hydrogen, halogen, formyl, carbamoyl, cyano,    trifluoromethyl, trifluoro-methoxy, nitro, (C₁-C₆)-alkyl,    (C₁-C₆)-alkoxy, (C₁-C₆)-alkylthio, (C₃-C₈)-cycloalkyl, 4- to    8-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl,    where phenyl and heteroaryl are optionally substituted by halogen,    (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, amino, mono- or    di-(C₁-C₄)-alkylamino, (C₁-C₄)-alkanoylamino or    (C₁-C₄)-alkanesulfonylamino.

The radicals R² and R³ in the general formula (I) may be bondedindependently of one another to ring A or to the benzene ring. Theradicals R² and R³ are preferably bonded to ring A.

The compounds of the invention may exist in stereoisomeric forms whicheither are related as image and mirror image (enantiomers) or which arenot related as image and mirror image (diastereomers). The inventionrelates both to the enantiomers or diastereomers or to respectivemixtures thereof. These mixtures of enantiomers and diastereomers can beseparated in a known manner into the stereoisomerically pureconstituents.

The compounds of the invention may also exist in the form of theirsalts, hydrates and/or solvates.

Salts which are preferred for the purposes of the invention arephysiologically acceptable salts of the compounds of the invention.

Physiologically acceptable salts of the compounds of the invention maybe acid addition salts of the compounds with mineral acids, carboxylicacids or sulfonic acids. Particularly preferred examples are salts withhydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid,benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionicacid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acidor benzoic acid.

However, salts which may be mentioned are also salts with conventionalbases, such as, for example, alkali metal salts (e.g. sodium orpotassium salts), alkaline earth metal salts (e.g. calcium or magnesiumsalts) or ammonium salts derived from ammonia or organic amines such as,for example, diethylamine, triethylamine, ethyldiisopropylamine,procaine, dibenzylamine, N-methylmorpholine, dihydroabiethylamine,1-ephenamine or methylpiperidine.

Hydrates of the compounds of the invention are stoichiometriccompositions of the compounds or its salts with water.

Solvates of the compounds of the invention are stoichiometriccompositions of the compounds or its salts with solvent.

For the purposes of the present invention, the substituents generallyhave the following meaning:

(C₁-C₄)-Alkanoylamino is a straight-chain or branched alkanoylaminoradical having 1 to 4 carbon atoms. A straight-chain or branchedalkanoylamino radical having 1 to 3 carbon atoms is preferred. Preferredexamples which may be mentioned are: formylamino, acetylamino,propanoylamino, n-butanoylamino, i-butanoylamino.

(C₁-C₆)- and (C₁-C₄)-alkoxy are a straight-chain or branched alkoxyradical having, respectively, 1 to 6 and 1 to 4 carbon atoms. Preferenceis given to a straight-chain or branched alky radical having 1 to 4,particularly preferably having 1 to 3, carbon atoms. Preferred exampleswhich may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy,tert-butoxy, n-pentoxy and n-hexoxy.

(C₁-C₆)- and (C₁-C₄)-alkyl are a straight-chain or branched alkylradical having, respectively, 1 to 6 and 1 to 4 carbon atoms. Preferenceis given to a straight-chain or branched alkyl radical having 1 to 4,particularly preferably having 1 to 3, carbon atoms. Preferred exampleswhich may be mentioned are: methyl, ethyl, n-propyl, isopropyl,tert-butyl, n-pentyl and n-hexyl.

Mono-(C₁-C₄)-alkylamino is a straight-chain or branched alkylaminoradical having 1 to 4 carbon atoms. A straight-chain or branchedalkylamino radical having 1 to 3 carbon atoms is preferred. Preferredexamples which may be mentioned are: methylamino, ethylamino,n-propylamino, isopropylamino, tert-butylamino.

Di-(C₁-C₄)-alkylamino is a straight-chain or branched dialkylaminoradical, where the alkyl radicals may be identical or different and eachcontain 1 to 4 carbon atoms. A straight-chain or branched dialkylaminoradical where the alkyl radical in each case contains 1 to 3 carbonatoms is preferred. Preferred examples which may be mentioned are:dimethylamino, diethylamino, di-n-propylamino, diisopropylamino,di-t-butylamino, di-n-pentylamino, di-n-hexylamino, ethylmethylamino,isopropylmethylamino, n-butylethylamino.

(C₁-C₄)-Alkanesulfonylamino are a straight-chain or branchedalkanesulfonylamino radical having 1 to 4 carbon atoms. A straight-chainor branched alkanesulfonylamino radical having 1 to 3 carbon atoms ispreferred. Preferred examples which may be mentioned are:methanesulfonylamino, ethanesulfonylamino, n-propanesulfonylamino,isopropanesulfonylamino, tert-butanesulfonylamino.

(C₁-C₆)-Alkylthio is a straight-chain or branched alkylthio radicalhaving 1 to 6 carbon atoms. Preference is given to a straight-chain orbranched alkylthio radical having 1 to 4, particularly preferably having1 to 3, carbon atoms. Preferred examples which may be mentioned are:methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio,n-pentylthio and n-hexylthio.

The azabicyclo[m.n.o]alkyl radical having 7 to 11 ring atoms ispreferably bonded via a carbon ring atom to the adjacent amide nitrogenatom. The nitrogen ring atom and the amide nitrogen atom are preferablynot located on the same carbon ring atom. Azabicyclo[m.n.o]alkylradicals in which the nitrogen ring atom and the amide nitrogen atom areseparated by two carbon ring atoms are particularly preferred. Examplesof azabicyclo[m.n.o]alkyl radicals which may be mentioned are:8-aza-bicyclo[3.2.1]octyl (tropane), 1-azabicyclo[3.2.1]octyl(isotropane), 8-aza-bicyclo[3.3.1]nonyl (granatane),1-azabicyclo[3.3.1]nonyl (isogranatane), 1-aza-bicyclo[2.2.2]octyl(quinuclidine), 2-azabicyclo[2.2.2]octyl (isoquinuclidine).

(C₃-C₈)-Cycloalkyl is cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl,cycloheptyl or cyclooctyl. Those which may be mentioned as preferredare: cyclopropyl, cyclopentyl and cyclohexyl.

Halogen is fluorine, chlorine, bromine and iodine. Fluorine, chlorineand bromine are preferred. Fluorine and chlorine are particularlypreferred.

5- to 6-membered heteroaryl is an aromatic radical having 5 to 6 ringatoms and up to 4 heteroatoms from the series S, O and/or N. Theheteroaryl radical may be bonded via a carbon atom or heteroatom.Preferred examples which may be mentioned are: thienyl, furyl, pyrrolyl,thiazolyl, oxazolyl, imidazolyl, tetrazolyl, pyridyl, pyrimidinyl, andpyridazinyl.

4- to 8-membered heterocyclyl is a mono- or polycyclic, heterocyclicradical having 4 to 8 ring atoms and up to 3, preferably 1, heteroatomsor hetero groups from the series N, O, S, SO, SO₂. Mono- or bicyclicheterocyclyl is preferred. Monocyclic carbocyclyl is particularlypreferred. N and O are preferred heteroatoms. The heterocyclyl radicalsmay be saturated or partially unsaturated. Saturated heterocyclylradicals are preferred. The heterocyclyl radicals may be bonded via acarbon atom or a heteroatom. 5- to 7-membered monocyclic saturatedheterocyclyl radicals having up to two heteroatoms from the series O, Nand S are particularly preferred. Preferred examples which may bementioned are: oxetan-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl,pyrrolinyl, tetrahydrofuranyl, tetrahydrothienyl, pyranyl, piperidinyl,thiopyranyl, morpholinyl, perhydroazepinyl.

If radicals in the compounds of the invention are optionallysubstituted, the radicals may, unless specified otherwise, have one ormore identical or different substituents. Substitution by up to threeidentical or different substituents is preferred.

Preferred compounds of the general formula (I) are those in which

-   R¹ is an azabicyclo[m.n.o]alkyl radical having 7 to 9 ring atoms, in    which m, n and o are identical or different and are 0, 1, 2 or 3,    and where the radical is optionally substituted by methyl or ethyl,-   and the ring A, R² and R³ have the meaning indicated above.

Particularly preferred compounds of the general formula (I) are those inwhich

-   R¹ is 1-azabicyclo[2.2.2]oct-3-yl,-   and the ring A, R² and R³ have the meaning indicated above.

Likewise preferred compounds of the general formula (I) are those inwhich

-   the ring A is pyrido,-   and R¹, R² and R³ have the meaning indicated above.

Particularly preferred compounds of the general formula (I) are those inwhich

-   the ring A together with the fused-on benzene residue is    quinolin-6-yl,-   and R¹, R² and R³ have the meaning indicated above.

Likewise preferred compounds of the general formula (I) are those inwhich

-   R² and R³ are identical or different and are radicals selected from    the group of hydrogen, halogen, cyano, trifluoromethyl, methyl and    ethyl,-   and the ring A and R¹ have the meaning indicated above.

Particularly preferred compounds of the general formula (I) are those inwhich

-   R² and R³ are identical or different and are radicals selected from    the group of hydrogen, halogen and methyl,-   and the ring A and R¹ have the meaning indicated above.

Combinations of two or more of the abovementioned preferred ranges arevery particularly preferred.

Likewise very particularly preferred are compounds of the generalformula (I) in which

-   R¹ is 1-azabicyclo[2.2.2]oct-3-yl,-   the ring A together with the fused-on benzene residue is    quinolin-5-yl or quinolin-6-yl, and-   R² and R³ are identical or different and are radicals selected from    the group of hydrogen, fluoro, chloro, and methyl.

The invention further relates to processes for preparing the compoundsof the formula (I), characterized in that

-   compounds of the general formula (II)

R¹—NH₂   (II)

-   in which R¹ has the abovementioned meaning,-   are reacted with a compound of the general formula (III)

in which

-   the ring A, R² and R³ have the abovementioned meaning, and-   X is hydroxyl or a suitable leaving group,-   in an inert solvent, where appropriate in the presence of a    condensing agent, and where appropriate in the presence of a base.

If X is a leaving group, chloro, mesyloxy and isobutyloxycarbonyloxy,especially chloro, are preferred.

Examples of inert solvents are halohydrocarbons such as methylenechloride, trichloromethane, tetrachloromethane, trichloroethane,tetrachloroethane, 1,2-di-chloroethane or trichloroethylene, ethers suchas diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran,glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbonssuch as benzene, xylene, toluene, hexane, cyclohexane or petroleumfractions, or other solvents such as nitromethane, ethyl acetate,acetone, dimethylformamide, dimethylacetamide, 1,2-dimethoxyethane,dimethyl sulfoxide, acetonitrile or pyridine, with preference fortetrahydrofuran, dimethylformamide or chloroform.

Condensing agents are, for example, carbodiimides such as, for example,N,N′-diethyl-, N,N′-dipropyl-, N,N′-dicyclohexylcarbodiimide,N-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC),N-cyclo-hexylcarbodiimide-N′-propyloxymethylpolystyrene(PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfateor 2-tert-butyl-5-methylisoxazolium perchlorate, or acylamino compoundssuch as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, orpropanephosphonic anhydride, or isobutyl chloroformate, orbis(2-oxo-3-oxazolidinyl)phosphoryl chloride orbenzotriazolyloxy-tri(dimethyl-amino)phosphonium hexafluorophosphate, orO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TPTU) orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) orbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP), or mixtures thereof.

It may be advantageous where appropriate to use these condensing agentsin the presence of an auxiliary nucleophile such as, for example,1-hydroxy-benzotriazole (HOBt).

Examples of bases are alkali metal carbonates such as, for example,sodium or potassium carbonate or bicarbonate, or organic bases such astrialkylamines, e.g. triethylamine, or N-methylmorpholine,N-methylpiperidine, 4-dimethylamino-pyridine or diisopropylethylamine.

Particular preference is given to the combination ofN-(3-dimethylamino-isopropyl)-N′-ethylcarbodiimide hydrochloride (EDC)and 1-hydroxybenzotriazole (HOBt) in dimethylformamide.

The process of the invention is preferably carried out in a temperaturerange from room temperature to 50° C. under atmospheric pressure.

The compounds of the general formulae (II) and (III) are known or can besynthesized by known processes from the appropriate precursors (cf., forexample, “Comprehensive Heterocyclic Chemistry”, Katritzki et al.,editors; Elsevier, 1996).

Thus, for example, quinolinecarboxylic acids [X¹ is hydroxyl and thering A is [b]pyrido in compounds of the general formula (III)] can beobtained by oxidizing the corresponding methylquinolines (Miller et al.Chem. Ber. 1890, 23, 2263 ff.) or the corresponding aldehydes (Howitz etal. Justus Liebigs Ann. Chem. 1913, 396, 37) with suitable oxidizingagents such as, for example, Cr₂O₃.

A further possibility is, for example, to obtain 6-quinolinecarboxylicacids by reacting 4-aminobenzoic acid with suitable enones (John et al.J. Prakt. Chem. 1925, 111, 95), as illustrated by way of example by thefollowing synthetic scheme.

An alternative possibility is to prepare quinolinecarboxamides of theinvention by reacting the corresponding iodine- and amino-substitutedbenzamides in the presence of suitable catalysts with allyl alcohols andpropargyl alcohols (cf. Kuo et al. Tetrahedron Lett. 1991, 32, 569), asillustrated by way of example by the following synthetic scheme.

The compounds of the invention of the general formula (I) are suitablefor use as medicaments for the treatment and/or prophylaxis of diseasesin humans and/or animals.

The compounds of the invention show a valuable range of pharmacologicaleffects which could not have been predicted.

They are notable as ligands, especially agonists, at the α7 nAChR.

The compounds of the invention can, because of their pharmacologicalproperties, be employed alone or in combination with other activeingredients for the treatment and/or prevention of cognitiveimpairments, especially of Alzheimer's disease. Because of theirselective effect as α7 nAChR agonists, the compounds of the inventionare particularly suitable for improving perception, concentration,learning or memory, especially after cognitive impairments like thoseoccurring for example in situations/diseases/syndromes such as mildcognitive impairment, age-associated learning and memory impairments,age-associated memory loss, vascular dementia, craniocerebral trauma,stroke, dementia occurring after strokes (post-stroke dementia),post-traumatic craniocerebral trauma, general concentration impairments,concentration impairments in children with learning and memory problems,attention deficit hyperactivity disorder, Alzheimer's disease, vasculardementia, Lewy body dementia, dementia with degeneration of the frontallobes, including Pick's syndrome, Parkinson's disease, progressivenuclear palsy, dementia with corticobasal degeneration, amyotrophiclateral sclerosis (ALS), Huntington's disease, multiple sclerosis,thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia,schizophrenia, schizophrenia with dementia or Korsakoffs psychosis.

The compounds of the invention can be employed alone or in combinationwith other medicaments for the prophylaxis and treatment of acute and/orchronic pain (for a classification, see “Classification of Chronic Pain,Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms”,2nd edition, Meskey and Begduk, editors; IASP Press, Seattle, 1994),especially for the treatment of cancer-induced pain and chronicneuropathic pain like, for example, that associated with diabeticneuropathy, postherpetic neuralgia, peripheral nerve damage, centralpain (for example as a consequence of cerebral ischemia) and trigeminalneuralgia, and other chronic pain such as, for example, lumbago,backache (low back pain) or rheumatic pain. In addition, thesesubstances are also suitable for the therapy of primary acute pain ofany origin and of secondary states of pain resulting therefrom, and forthe therapy of states of pain which were formerly acute and have becomechronic.

The in vitro effect of the compounds of the invention can be shown inthe following assays:

1. Determination of the Affinity of Test Substances for α7 nAChR byInhibition of [³H]-methyllycaconitine Binding to Rat Brain Membranes

The [³H]-methyllycaconitine binding assay is a modification of themethod described by Davies et al. (Neuropharmacol, 1999, 38, 679-690).

Rat brain tissue (hippocampus or whole brain) is homogenized inhomogenization buffer (10% w/v) (0.32 M sucrose, 1 mM EDTA, 0.1 mMphenylmethylsulfonyl fluoride (PMSF), 0.01% (w/v) NaN₃, pH 7.4, 4° C.)at 600 rpm in a glass homogenizer. The homogenate is centrifuged(1000×g, 4° C., 10 min) and the supernatant is removed. The pellet isresuspended (20% w/v) and the suspension is centrifuged (1000×g, 4° C.,10 min). The two supernatants are combined and centrifuged (15 000×g, 4°C., 30 min). This pellet is referred to as the P2 fraction.

The P2 pellet is twice washed with binding buffer (50 mM Tris-HCl, 1 mMMgCl₂, 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, pH 7.4) and centrifuged (15000×g, 4° C., 30 min).

The P2 membranes are resuspended in binding buffer and incubated in avolume of 250 μl (amount of membrane protein 0.1-0.5 mg) in the presenceof 1-5 nM [³H]-methyllycaconitine, 0.1% (w/v) BSA (bovine serum albumin)and various concentrations of the test substance at 21° C. for 2.5 h.Nonspecific binding is determined by incubation in the presence of 1 μMα-bungarotoxin or 100 μM nicotine or 10 μM MLA (methyllycaconitine).

The incubation is stopped by adding 4 ml PBS (20 mM Na₂HPO₄, 5 mMKH₂PO₄, 150 mM NaCl, pH 7.4, 4° C.) and filtering through type A/E glassfibre filters (Gelman Sciences) which have previously been placed in0.3% (v/v) polyethyleneimine (PEI) for 3 h. The filters are washed twicewith 4 ml of PBS (4° C.), and the bound radioactivity is determined byscintillation measurement. All the assays are carried out in triplicate.The dissociation constant K_(i) of the test substance was determinedfrom the IC₅₀ of the compounds (concentration of the test substance atwhich 50% of the ligand bound to the receptor is displaced), thedissociation constant K_(D) and the concentration L of[³H]-methyllycaconitine (K_(i)=IC₅₀/(1+L/K_(D))).

In place of [³H]-methyllycaconitine it is also possible to employ otherα7 nAChR-selective radioligands such as, for example,^([125)I]-α-bungarotoxin or nonselective nAChR radioligands togetherwith inhibitors of other nAChRs.

The suitability of the compounds of the invention for the treatment ofcognitive impairments can be shown in the following animal models:

2. Object Recognition Test

The object recognition test is a memory test. It measures the ability ofrats (and mice) to distinguish between familiar and unfamiliar objects.

The test is carried out as described (Blokland et al., NeuroReport 1998,9, 4205-4208; Ennaceur, A., Delacour, J., Behav. Brain Res. 1988, 31,47-59; Ennaceur, A., Meliani, K., Psychopharmacology 1992, 109, 321-330;and Prickaerts et al., Eur. J. Pharmacol. 1997, 337, 125-136).

In a first run, a rat is confronted in an otherwise empty observationarena of relatively large size by two identical objects. The rat willinvestigate, i.e. sniff round and touch, both objects extensively. In asecond run, after an interval of 24 hours, the rat is put in theobservation arena again. One of the familiar objects has now beenreplaced by a new, unfamiliar object. If a rat recognizes the familiarobject, it will concentrate on investigating the unfamiliar object.However, after 24 hours, a rat has normally forgotten which object itinvestigated in the first run, and it will therefore inspect bothobjects to the same extent. Administration of a substance with alearning- and memory-improving effect may lead to a rat recognizing theobject seen in the first run 24 hours previously as familiar. It willinvestigate the new, unfamiliar object in more detail than the familiarone. This memory ability is expressed in a discrimination index. Adiscrimination index of zero means that the rat investigates bothobjects, the old and the new, for equal times; that is to say it has notrecognized the old object and reacts to both objects as if they wereunfamiliar and new. A discrimination index greater than zero means thatthe rat inspects the new object for longer than the old one; that is tosay the rat has recognized the old object.

3. Social Recognition Test:

The social recognition test is a test to examine the learning- ormemory-improving effect of test substances.

Adult rats housed in groups are placed singly in test cages 30 minutesbefore the start of the test. Four minutes before the start of the test,the test animal is put in an observation box. After this adaptationtime, a juvenile animal is put in with the test animal and the totaltime for which the adult animal investigates the juvenile animal ismeasured for 2 minutes (trial 1). All behaviors clearly directed at theyoung animal are measured, i.e. anogenital inspection, pursuit and furcare, during which the old animal is no further than 1 cm from the younganimal. The juvenile animal is then taken out, and the adult is left inits test cage (for 24-hour retention, the animal is returned to its homecage). The test animal is treated with test substance before or afterthe first test. Depending on the timing of the treatment, the learningor the storage of the information about the young animal can beinfluenced by the substance. After a fixed period (retention), the testis repeated (trial 2). A larger difference between the investigationtimes measured in trials 1 and 2 means that the adult animal hasremembered the young animal better.

The compounds of the invention of the general formula (I) are suitablefor use as medicaments for humans and animals.

The present invention also includes pharmaceutical preparations which,besides inert, nontoxic, pharmaceutically suitable excipients andcarriers, contain one or more compounds of the general formula (I), orwhich consist of one or more compounds of the general formula (I), andprocesses for producing these preparations.

The compounds of the formula (I) are to be present in these preparationsin a concentration of from 0.1 to 99.5% by weight, preferably from 0.5to 95% by weight, of the complete mixture.

Besides the compounds of the formula (I), the pharmaceuticalpreparations may also contain other active pharmaceutical ingredients.

The abovementioned pharmaceutical preparations can be produced by knownmethods in a conventional way, for example using the excipient(s) orcarrier(s).

The novel active ingredients can be converted in a known manner intoconventional formulations such as tablets, coated tablets, pills,granules, aerosols, syrups, emulsions, suspensions and solutions, usinginert, nontoxic, pharmaceutically suitable carriers or solvents. Inthese cases, the therapeutically active compound should in each case bepresent in a concentration of about 0.5 to 90% by weight of the completemixture, i.e. in amounts which are sufficient to reach the stated doserange.

The formulations are produced for example by extending the activeingredients with solvents and/or carriers, where appropriate with use ofemulsifiers and/or dispersants, it being possible, for example whenwater is used as diluent, where appropriate to use organic solvents asauxiliary solvents.

Administration takes place in a conventional way, preferably orally,transdermally or parenterally, especially perlingually or intravenously.However, it can also take place by inhalation through the mouth or nose,for example with the aid of a spray, or topically via the skin.

It has generally proved advantageous to administer amounts of about0.001 to 10 mg/kg, on oral administration preferably about 0.005 to 3mg/kg, of body weight to achieve effective results.

It may, nevertheless, be necessary where appropriate to deviate from thestated amounts, in particular as a function of the body weight or of themode of administration, of the individual behavior toward themedicament, the nature of its formulation and the time or interval overwhich administration takes place. Thus, it may be sufficient in somecases to make do with less than the aforementioned minimum amount,whereas in other cases the stated upper limit must be exceeded. Wherelarger amounts are administered, it may be advisable to divide theseinto a plurality of single doses over the day.

Abbreviations:

-   DMF N,N-Dimethylformamide-   DMSO Dimethyl sulfoxide-   HOBt 1-Hydroxy-1H-benzotriazole x H₂O-   NMR Nuclear magnetic resonance spectroscopy-   RT Room temperature-   TBTU O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    tetrafluoroborate-   THF Tetrahydrofuran

Starting Compounds EXAMPLE 1A 4-Amino-3-iodobenzoic acid

A solution of 3.00 g (10.8 mmol) of methyl 4-amino-3-iodobenzoate and1.30 g (54.1 mmol) of lithium hydroxide in 150 ml of a dioxane/watermixture (1:1) was stirred at room temperature for 6 h. The dioxane wasdistilled off in vacuo, and the remaining aqueous phase was adjusted topH 5 with 1 M hydrochloric acid. The precipitate was filtered off withsuction and washed with water. 2.80 g (98%) of the title compound wereobtained as a solid.

HPLC (Kromasil RP-18, 60×2.1 mm, eluent=A: H₂O+5 mL HClO₄/L; B:acetonitrile; gradient=0-4.5 min 98% A—90% B; 4.5-6.5 min 90% B; 0.75mL/min; temp.: 30° C., UV detection at 210 nm): Rt=3.51 min

¹H-NMR (300 MHz in D₆-DMSO) δ=5.98 (s, 2H), 6.74 (d, 1H), 7.63 (m, 1H),8.10 (s, 1H), 12.33 (s, broad, 1H)

MS (ESI+): m/z=281 [M+NH₄]⁺

EXAMPLE 2A 4-Amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-3-iodobenzamide

A solution of 2.04 g (10.3 mmol) of 3-aminoquinuclidine dihydrochloride,2.70 g (10.3 mmol) of 4-amino-3-iodobenzoic acid, 1.39 g (10.3 mmol) ofHOBt, 2.16 g (11.3 mmol) of EDC and 6.63 g (51.3 mmol) ofN,N-diisopropylethylamine in 150 ml of DMF was stirred at roomtemperature for 16 h. 300 ml of water were added, and the aqueous phasewas extracted three times with 300 ml of ethyl acetate each time. Thecombined organic phases were dried over sodium sulfate and the solventwas distilled off in vacuo. The residue was purified on a flash column(mobile phase: dichloromethane/methanol/triethylamine 90:10:0.2). 3.45 g(87%) of the desired title compound were obtined.

HPLC (conditions as in Example 1A): Rt=3.29 min

¹H-NMR (200 MHz in D₆-DMSO) δ=1.18-1.87 (m, 5H), 2.58-3.13 (m, 6H), 3.49(m, broad, 1H), 3.89 (m, 1H), 5.75 (m, 3H), 6.72 (d, 1H), 7.63 (dd, 1H),7.92 (d, 1H), 8.12 (d, 1H)

MS (ESI+): m/z=372 [M+H]⁺

EXAMPLE 3A N-(1-Azabicyclo[2.2.2]oct-3-yl)-4-iodo-3-nitrobenzamide

A solution of 3.08 g (24.4 mmol) of 3-aminoquinuclidine dihydrochloride,7.60 g (24.4 mmol) of 4-iodo-3-nitrobenzoyl chloride, 9.88 g (97.6 mmol)of triethylamine in 150 ml of DMF was stirred at room temperatureovernight. The solvent was distilled off in a rotary evaporator, theresidue was taken up in 200 ml of dichloromethane, and 200 ml of asaturated sodium bicarbonate solution were added. The organic phase wasdried over sodium sulfate, and the solvent was distilled off in vacuo.2.20 g (22.5%) of the desired title compound were obtained.

HPLC (conditions as in Example 1A): Rt=3.72 min.

¹H-NMR (300 MHz in CDCl₃) δ=1.24-1.78 (m, 5H), 2.05 (m, 1H), 2.61 (m,1H), 2.89 (m, 3H), 3.46 (m, 1H), 4.15 (m, 1H), 6.24 (m, 1H), 7.67 (dd,1H), 8.14 (d, 1H), 8.20 (d, 1H).

MS (ESI+): m/z=402 [M+H]⁺

EXAMPLE 4A 3-Amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-4-iodobenzamide

A solution of 100 mg (0.25 mmol) ofN-(1-azabicyclo[2.2.2]oct-3-yl)-4-iodo-3-nitrobenzamide and 281 mg (1.25mmol) of tin(II) chloride dihydrate in 5 ml of DMF was stirred at roomtemperature for 6 h. The solvent was distilled off in a rotaryevaporator, the residue was taken up in 10 ml of dichloromethane, and 10ml of aqueous 1 M sodium hydroxide solution were added. The organicphase was dried over sodium sulfate, and the solvent was distilled offin a rotary evaporator. 91 mg (98%) of the desired title compound wereobtained.

HPLC (conditions as in Example 1A): Rt=3.28 min.

¹H-NMR (300 MHz in D₆-DMSO) δ=1.21-1.85 (m, 5H), 2.64 (m, 4H), 2.85 (m,1H), 3.05 (m, 1H), 3.89 (m, 1H), 5.34 (s, broad, 2H), 6.78 (dd, 1H),7.15 (m, 1H), 7.60 (d, 1H), 8.13 (d, 1H).

MS (ESI+): m/z=372 [M+H]⁺

Exemplary Embodiments EXAMPLE 1N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-quinolinecarboxamide hydrochloride

Firstly, 319 mg (0.99 mmol) of TBTU and 137 mg (1.01 mmol) of HOBt areadded to a solution of 182 mg (1.05 mmol) of quinoline-6-carboxylic acidand diiso-propylethylamine (620 mg, 4.8 mmol) in 4 mL of DMF at RT, andthen 200 mg (1.0 mmol) of 3-aminoquinuclidine dihydrochloride are added.The mixture is stirred at RT for 4 h. For a workup, it is concentratedand taken up in a mixture of chloroform and excess aqueous NaOH. Thephases are separated and the aqueous phase is back-extracted severaltimes with chloroform. The combined organic phases are dried over sodiumsulfate and concentrated, and the crude product is chromatographed on asilica gel column (mobile, chloroform:methanol: conc. NH₃=100:20:4). Theresulting product is taken up in THF, excess HCl in diethyl ether isadded, and the mixture is concentrated and dried under high vacuum. 136mg (47% yield) of the hydrochloride are obtained.

¹H-NMR (300 MHz, CD₃OD) δ=9.30 (m, 2H); 8.95 (s, 1H); 8.60 (d, 1H), 8.32(d, 1H); 8.15 (m, 1H); 4.55 (m, 1H), 3.85 (m, 1H); 3.60-3.30 (m, 5H);2.50-1.90 (m, 5H).

MS (ESI+): m/z=282 ([M+H]⁺ of the free base)

EXAMPLE 2 N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-phenazinecarboxamide

Prepared in analogy to the method for Example 1 starting from 236 mg ofphenazine-2-carboxylic acid and 200 mg of 3-aminoquinuclidinedihydrochloride. 84 mg (25% yield) of the free base were obtained afterchromatographic separation.

¹H-NMR (in DMSO-d₆) δ=8.85 (s, 1H); 8.75 (d, J=7 Hz, 1H); 8.30 (m, 4H);8.00 (m, 2H); 4.05 (m, 1H); 3.2-2.7 (m, 6H); 2.0-1.3 (m, 5H).

MS (ESI+): m/z=333 [M+H]⁺

EXAMPLE 3 N-(1-Azabicyclo[2.2.2]oct-3-yl)-7-quinolinecarboxamidehydrochloride

Prepared in analogy to the method for Example 1 starting from 183 mg ofquinoline-7-carboxylic acid (Seibert et al. J. Am. Chem. Soc. 1946, 68,2721) and 200 mg of 3-aminoquinuclidine dihydrochloride. 227 mg (71%yield) of the hydro-chloride were obtained.

¹H-NMR (300 MHz in DMSO-d₆) δ=10.5 (s, 1H); 9.15 (m, 2H); 8.70 (m, 2H),8.20 (m, 2H); 7.80 (m, 1H); 4.40 (m, 1H); 3.65 (m, 1H), 3.45-3.10 (m,5H); 2.30-1.65 (m, 5H).

MS (ESI+): m/z=282 ([M+H]⁺ of the free base)

EXAMPLE 4 N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-quinolinecarboxamidehydrochloride

Prepared in analogy to Example 1 starting from(3R)-1-azabicyclo[2.2.2]oct-3-ylamine. The ¹H-NMR and MS data wereidentical to Example 1.

EXAMPLE 5 N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-ethyl-7-quinolinecarboxamide

A solution of 30 mg (0.08 mmol) of Example 4A, 0.32 mmol of1-penten-3-ol, 0.5 mg (10 mol %) of palladium(II) acetate, 22.4 mg (0.08mmol) of tetrabutyl-ammonium chloride, 0.6 mg (10 mol %) oftri-tert-butylphosphine and 28 mg (0.20 mmol) of potassium carbonate in2 ml of DMF was stirred at 100° C. in an argon atmosphere for 72 h. Thesolvent was distilled off and the residue was taken up in methanol. Itwas purified by thick-layer chromatography (mobile phase:dichloromethane/methanol/triethylamine 80:20:2).

The title compound was obtained in 12% yield.

HPLC (conditions as in Example 1A): Rt=3.00 min.

¹H-NMR (400 MHz in D₆-DMSO) δ=1.35 (t, 3H), 1.21-2.01 (m, 5H), 2.96 (q,2H), 2.82-3.12 (m, 5H), 4.11 (m, 1H), 7.52 (d, 1H), 7.95 (m, 2H), 8.31(d, 1H), 8.54 (s, 1H), 8.64 (d, 1H).

MS (ESI+): m/z=310 [M+H]⁺

EXAMPLE 6 N-(1-Azabicyclo[2.2,2]oct-3-yl)-2-ethyl-6-quinolinecarboxamide

Example 2A was reacted with 1-penten-3-ol in analogy to the method forExample 5. The title compound was obtained in 36% yield.

LC/MS (Kromasil RP-18, 5 μm, 2.1×150 mm, eluent=A: acetonitrile B:H₂O+0.23 g 30% HCl/1 water; gradient=0-2.5 min 2% A—95% A; 2.5-5 min 95%A; flow rate=0.9 mL/min; temp.: 70° C., UV detection at 210 nm): Rt=1.71min; MS (ESI+): m/z=310 [M+H]⁺.

¹H-NMR (400 MHz in D₆-DMSO) δ=1.32 (t, 3H), 1.25-2.22 (m, 5H), 2.76 (m,4H), 2.97 (m, 5H), 4.06 (m, 1H), 7.52 (d, 1H), 7.98 (d, 1), 8.12 (dd,1H), 8.36 (d, 1H), 8.43 (s, 1H), 8.52 (d, 1H).

EXAMPLE 7N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-methyl-7-quinolinecarboxamide

Example 4A was reacted with 1-buten-3-ol in analogy to the method forExample 5. The title compound was obtained in 21% yield.

LC/MS (conditions as in Example 6): Rt=1.70 min; MS (ESI+): m/z=296[M+H]⁺.

¹H-NMR (400 MHz in D₆-DMSO) δ=1.38-1.99 (m, 5H), 2.68 (s, 3H), 2.82 (m,4H), 3.01 (m, 1H), 4.10 (m, 1H), 7.50 (d, 1H), 7.96 (m, 2H), 8.30 (d,1H), 8.51 (s, 1H), 8.60 (s, 1H).

EXAMPLE 8N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-methyl-6-quinolinecarboxamide

Example 2A was reacted with 1-buten-3-ol in analogy to the method forExample 5. The title compound was obtained in 29% yield.

LC/MS (conditions as in Example 6): Rt=0.57 min; MS (ESI+): m/z=296[M+H]⁺.

EXAMPLE 9N-(1-Azabicyclo[2.2.2]oct-3-yl)-4-methyl-6-quinolinecarboxamide

Example 2A was reacted with 2-butyn-1-ol in analogy to the method forExample 5. The title compound was obtained in 8% yield.

LC/MS (conditions as in Example 6): Rt=0.56 min; MS (ESI+): m/z=296[M+H]⁺.

EXAMPLE 10N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-propyl-6-quinolinecarboxamide

Example 2A was reacted with 1-hexen-3-ol in analogy to the method forExample 5. The title compound was obtained in 23% yield.

LC/MS (conditions as in Example 6): Rt=1.77 min; MS (ESI+): m/z=324[M+H]⁺.

¹H-NMR (400 MHz in D₆-DMSO) δ=0.95 (t, 3H), 1.24-1.65 (m, 4H), 1.85 (m,4H), 2.70 (m, 3H), 2.91 (m, 3H), 3.15 (m, 1H), 4.01 (m, 1H), 5.76 (m,1H), 7.50 (d, 1H), 7.96 (m, 1H), 8.12 (d, 1H), 8.38 (d, 1H), 8.47 (m,2H).

EXAMPLE 11N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-ethyl-4-methyl-6-quinolinecarboxamide

Example 2A was reacted with 2-hexyn-4-ol in analogy to the method forExample 5. The title compound was obtained in 16% yield.

LC/MS (conditions as in Example 6): Rt=2.06 min; MS (ESI+): m/z=324[M+H]⁺.

¹H-NMR (400 MHz in D₆-DMSO) δ=1.31 (t, 3H), 1.61 (m, 2H), 1.90 (m, 2H),2.71 (m, 8H), 2.91 (m, 4H), 3.17 (m, 1H), 4.01 (m, 1H), 7.39 (s, 1H),7.95 (d, 1H), 8.13 (m, 1H), 8.49 (m, 2H).

EXAMPLE 12N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-propyl-7-quinolinecarboxamide

Example 4A was reacted with 1-hexen-3-ol in analogy to the method forExample 5. The title compound was obtained in 12% yield.

LC/MS (conditions as in Example 6): Rt=1.73 min; MS (ESI+): m/z=324[M+H]⁺.

¹H-NMR (400 MHz in D₆-DMSO) δ=0.96 (t, 3H), 1.38 (m, 1H), 1.63 (m, 2H),1.87 (m, 5H), 2.75 (m, 5H), 2.93 (m, 3H), 3.20 (m, 1H), 4.05 (m, 1H),7.50 (d, 1H), 7.96 (m, 2H), 8.30 (m, 1H), 8.54 (s, 1H), 8.61 (d, 1H).

EXAMPLE 13N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-ethyl-4-methyl-7-quinolinecarboxamide

Example 4A was reacted with 2-hexyn-4-ol in analogy to the method forExample 5. The title compound was obtained in 15% yield.

LC/MS (conditions as in Example 6): Rt=1.73 min; MS (ESI+): m/z=324[M+H]⁺.

¹H-NMR (400 MHz in D₆-DMSO) δ=1.32 (t, 3H), 1.60 (m, 2H), 1.85 (m, 1H),2.70 (m, 8H), 2.92 (m, 4H), 3.12 (m, 1H), 4.02 (m, 1H), 7.40 (s, 1H),7.97 (d, 1H), 8.10 (d, 1H), 8.53 (m, 1H), 8.59 (d, 1H).

EXAMPLE 14N-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(tetrahydro-2H-pyran-2-yl)-6-quinoline-carboxamide

Example 2A was reacted with 3-(tetrahydro-2H-pyran-2-yl)-2-propyn-1-olin analogy to the method for Example 5. The title compound was obtainedin 12% yield.

LC/MS (conditions as in Example 6): Rt=1.78 min; MS (ESI+): m/z=366[M+H]⁺.

¹H-NMR (400 MHz in D₆-DMSO) δ=1.22-2.05 (m, 13H), 2.71 (m, 5H), 2.90 (m,2H), 3.17 (m, 1H), 3.76 (m, 1H), 4.00 (m, 1H), 4.16 (m, 1H), 5.18 (d,1H), 7.60 (d, 1H), 8.05 (d, 1H), 8.18 (d, 1H), 8.52 (s, 1H), 8.94 (d,1H).

EXAMPLE 15N-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(tetrahydro-2H-pyran-2-yl)-7-quinoline-carboxamide

Example 4A was reacted with 3-(tetrahydro-2H-pyran-2-yl)-2-propyn-1-olin analogy to the method for Example 5. The title compound was obtainedin 9% yield.

LC/MS (conditions as in Example 6): Rt=1.92 min; MS (ESI+): m/z=366[M+H]⁺.

EXAMPLE 16N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-phenyl-6-quinolinecarboxamide

Intermediate 2 was reacted with 3-phenyl-1-propen-3-ol in accordancewith the general method. The title compound was obtained in 38% yield.

LC/MS (conditions as in Example 6): Rt=1.94 min; MS (ESI+): m/z=358[M+H]⁺.

EXAMPLE 17N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-phenyl-7-quinolinecarboxamide

Example 4A was reacted with 3-phenyl-1-propen-3-ol in analogy to themethod for Example 5. The title compound was obtained in 24% yield.

LC/MS (conditions as in Example 6): Rt=1.95 min; MS (ESI+): m/z=358[M+H]⁺.

1) A compound of the formula (I)

in which R¹ is 1-azabicyclo[2.2.2]oct-3-yl, the ring A is pyrimido, andR² and R³ are identical or different and are radicals selected from thegroup of hydrogen, halogen, formyl, carbamoyl, cyano, trifluoromethyl,trifluoromethoxy, nitro, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy,(C₁-C₆)-alkylthio, (C₃-C₈)-cycloalkyl, 4- to 8-membered heterocyclyl,phenyl or 5- to 6-membered heteroaryl, where phenyl and heteroaryl areoptionally substituted by halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, amino,mono- or di-(C₁-C₄)-alkylamino, (C₁-C₄)-alkanoylamino or(C₁-C₄)-alkanesulfonylamino. or a salt thereof. 2) A compound of theformula (I)

in which R¹ is 1-azabicyclo[2.2.2]oct-3-yl, the ring A is optionallybenzo-fused pyrido, and R² and R³ are identical or different and areradicals selected from the group of hydrogen, halogen, formyl,carbamoyl, cyano, trifluoromethyl, trifluoromethoxy, nitro,(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkylthio, (C₃-C₈)-cycloalkyl, 4-to 8-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl, wherephenyl and heteroaryl are optionally substituted by halogen,(C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, amino, mono- or di-(C₁-C₄)-alkylamino,(C₁-C₄)-alkanoylamino or (C₁-C₄)-alkanesulfonylamino. or a salt thereof.3) A compound of the formula (I)

in which R¹ is 1-azabicyclo[2.2.2]oct-3-yl, the ring A is pyridazo, andR² and R³ are identical or different and are radicals selected from thegroup of hydrogen, halogen, formyl, carbamoyl, cyano, trifluoromethyl,trifluoromethoxy, nitro, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy,(C₁-C₆)-alkylthio, (C₃-C₈)-cycloalkyl, 4- to 8-membered heterocyclyl,phenyl or 5- to 6-membered heteroaryl, where phenyl and heteroaryl areoptionally substituted by halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, amino,mono- or di-(C₁-C₄)-alkylamino, (C₁-C₄)-alkanoylamino or(C₁-C₄)-alkanesulfonylamino. or a salt thereof. 4) A compound of theformula (I)

in which R¹ is 1-azabicyclo[2.2.2]oct-3-yl, the ring A is pyridazino,and R² and R³ are identical or different and are radicals selected fromthe group of hydrogen, halogen, formyl, carbamoyl, cyano,trifluoromethyl, trifluoromethoxy, nitro, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy,alkylthio, (C₃-C₈)-cycloalkyl, 4- to 8-membered heterocyclyl, phenyl or5- to 6-membered heteroaryl, where phenyl and heteroaryl are optionallysubstituted by halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, amino, mono- ordi-(C₁-C₄)-alkylamino, (C₁-C₄)-alkanoylamino or(C₁-C₄)-alkanesulfonylamino. or a salt thereof. 5) A compound having theIUPAC name: N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-quinolinecarboxamidehydrochloride; N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-phenazinecarboxamide;N-(1-Azabicyclo[2.2.2]oct-3-yl)-7-quinolinecarboxamide hydrochloride;N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-quinolinecarboxamidehydrochloride;N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-ethyl-7-quinolinecarboxamide;N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-ethyl-6-quinolinecarboxamide;N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-methyl-7-quinolinecarboxamide;N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-methyl-6-quinolinecarboxamide;N-(1-Azabicyclo[2.2.2]oct-3-yl)-4-methyl-6-quinolinecarboxamide;N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-propyl-6-quinolinecarboxamide;N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-ethyl-4-methyl-6-quinolinecarboxamide;N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-propyl-7-quinolinecarboxamide;N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-ethyl-4-methyl-7-quinolinecarboxamide;N-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(tetrahydro-2H-pyran-2-yl)-6-quinoline-carboxamide;N-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(tetrahydro-2H-pyran-2-yl)-7-quinoline-carboxamide;N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-phenyl-6-quinolinecarboxamide;N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-phenyl-7-quinolinecarboxamide; or asalt thereof.